Review Article | Published:

The BER necessities: the repair of DNA damage in human-adapted bacterial pathogens

Nature Reviews Microbiology volume 13, pages 8394 (2015) | Download Citation

Abstract

During colonization and disease, bacterial pathogens must survive the onslaught of the host immune system. A key component of the innate immune response is the generation of reactive oxygen and nitrogen species by phagocytic cells, which target and disrupt pathogen molecules, particularly DNA, and the base excision repair (BER) pathway is the most important mechanism for the repair of such oxidative DNA damage. In this Review, we discuss how the human-specific pathogens Mycobacterium tuberculosis, Helicobacter pylori and Neisseria meningitidis have evolved specialized mechanisms of DNA repair, particularly their BER pathways, compared with model organisms such as Escherichia coli. This specialization in DNA repair is likely to reflect the distinct niches occupied by these important human pathogens in the host.

Key points

  • Base excision repair (BER) is a highly conserved process that primarily repairs oxidative DNA damage, and human-adapted bacterial pathogens have evolved specialized mechanisms for BER.

  • Mycobacterium tuberculosis displays striking redundancy in the enzymes that prevent incorporation of oxidized guanines into the DNA backbone and excise nucleotides mispaired with this damaged base.

  • By contrast, Helicobacter pylori, which inhabits the gastric mucosa, has a minimal complement of BER enzymes. A network of enzymes recognize and repair DNA damage by BER in Neisseria meningitidis.

  • Expression of the BER enzymes is constitutive in Neisseria meningitidis, which might reflect the high selective pressure of oxidative stress in its habitat in the aerobic upper airways.

  • Further work is required to understand mechanisms of BER in other pathogens and related human commensal species, which should provide insights into whether specialization in BER contributes to colonization and/or human disease.

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Acknowledgements

Work in C.M.T.'s laboratory is supported by a Wellcome Trust Senior Investigator Award, the Medical Research Council and Action Medical Research.

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  1. Sir William Dunn School of Pathology, South Parks Road, University of Oxford, Oxford, OX1 3RE, UK.

    • Stijn van der Veen
    •  & Christoph M. Tang

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The authors declare no competing financial interests.

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Correspondence to Christoph M. Tang.

Glossary

Apurinic or apyrimidinic (AP) sites

Regions of the DNA that lack nucleobases, generally as a result of DNA damage, spontaneous loss or inefficient DNA repair.

Reactive oxygen species

(ROS). Reactive molecules that contain oxygen (such as superoxide, hydrogen peroxide and hydroxyl radicals), which damage macromolecules such as DNA, proteins and lipids.

Reactive nitrogen species

(RNS). Nitrogen-containing oxides, such as peroxynitrite and nitric oxide radicals, which are highly reactive molecules that damage DNA and proteins through oxidation and nitrosation reactions.

Phagocytosis

The mechanism by which phagocytes, such as macrophages and neutrophils, engulf and destroy microorganisms, foreign material and cellular debris.

Respiratory burst

Rapid release of reactive oxygen species and reactive nitrogen species from immune cells, such as macrophages and neutrophils, to attack invading microorganisms. It is initiated by the NADPH-dependent oxidase that converts oxygen into superoxide, which subsequently reacts with other molecules such as nitric oxide to form the highly reactive oxidants peroxynitrite and hydroxyl radials.

Activated neutrophils and macrophages

Neutrophils and macrophages that undergo morphological changes following triggers (such as cytokines) and that are able to extend pseudopods that assist phagocytosis. In addition, they can rapidly release reactive oxygen species and reactive nitrogen species in a 'respiratory burst', thereby killing engulfed microorganisms.

Superoxide anions

(O2). A common reactive form of oxygen that is generated when molecular oxygen gains an electron. It is a common intermediate in biological processes and is generated by phagocytes to kill microorganisms in a 'respiratory burst'.

Phagosome

Intracellular compartment of a phagocyte that contains phagocytised microorganisms, foreign material or cellular debris.

Chronic granulomatous disease

(CGD). A genetic deficiency of phagocyte oxidase components that is characterized by recurrent infections.

Hydroxyl radicals

(OH). Highly reactive oxygen-containing molecules that cause severe damage to macromolecules. They are produced by phagocytes through the conversion of water into superoxide and hydrogen peroxide to kill microorganisms in a 'respiratory burst'.

Fenton reaction

Reaction between hydrogen peroxide and iron salts, mostly via iron–sulfur protein clusters, which generates hydroxyl radicals.

Peroxynitrite

(ONOO). A highly reactive molecule that damages macromolecules, such as DNA and proteins, through oxidation and nitrosation reactions. In phagocytes, it is produced during the 'respiratory burst' through the reaction of superoxide with nitric oxide.

Deamination

Removal of an amine group from nucleobases, amino acids or other molecules.

Alkylation

Transfer of alkyl groups, such as a methyl group or chains with more carbons, between molecules.

β-elimination

Cleavage of the DNA backbone at the 3′ end of an apurinic or apyrimidinic site by a bifunctional DNA glycosylase after removal of a damaged nucleobase. Cleavage produces a 3′-unsaturated aldehyde and a 5′-phosphate group.

γ-elimination

Cleavage of the DNA backbone at the 5′ end of an apurinic or apyrimidinic (AP) site by a bifunctional DNA glycosylase. Cleavage removes the AP site and leaves a phosphate group at both termini.

SOS response

An inducible pathway in bacteria that is activated on the accumulation of single-stranded DNA as a result of DNA damage or the collapse of replication forks. This response typically involves DNA repair proteins and translesion DNA polymerases.

UvrABC complex

A multicomponent enzyme complex that has endonucleolytic activity and is involved in the nucleotide excision repair pathway.

Holliday junction

An assembly of four DNA strands that forms during certain types of genetic recombination.

Hypoxanthine

A deamination product of adenine that is highly mutagenic owing to its ability to base-pair with cytosine and adenine during replication.

Ethenocytosine

A highly mutagenic adduct that is formed by the alkylation of cytosine.

Phase variation

A heritable change in the level of expression of a protein. It often occurs through an alteration in repetitive DNA sequences.

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